Chronic pain and disability after war-related injuries and after trauma sustained in civilian settings are unexpectedly common. Chronic pain related to traumatic brain injury (TBI) in combination with peripheral injuries is particularly problematic, and we have no well-validated treatments. Potentially explaining the TBI- chronic pain relationship, data from both humans and animal models suggest that descending pain modulation is disrupted after TBI. Recently collected data using laboratory models of brain injury and TBI patients demonstrate the vulnerability of brainstem centers governing endogenous pain modulation. Histopathological and functional TBI studies suggest damage to the periaqueductal gray matter (PAG), a major endogenous pain control center, and the locus coeruleus (LC), a key structure providing descending noradrenergic inhibition to the spinal cord. Moreover, TBI alters the function of the rostral ventromedial medulla (RVM), a structure that provides both descending pain-facilitating and pain-inhibiting serotonergic fibers. Our main objective is, therefore, to evaluate endogenous pain regulatory mechanisms after TBI and pre-clinically test translatable approaches to pain control in this setting. In the first aim we evaluate the hypothesis that TBI disrupts descending pain modulation by altering descending noradrenergic and serotonergic circuits. The experimental approach uses a well-validated rat fluid percussion model of TBI studied along a broad time course to mimic sub-acute and chronic injuries. Highly selective and clinically available pharmacological tools targeting noradrenalin release, serotonergic tone and the stimulation of ?2-adrenergic, as well as 5-HT3 and 5-HT7 receptors will be employed. Outcomes will focus on the regulation of nociceptive thresholds and the efficiency of descending pain modulation circuits. In the second aim we evaluate the hypothesis that TBI injures neurons and promotes sustained neuro- inflammation in the LC and RVM as well as giving rise to functional changes in descending pain modulation. In addition to neuropathological evaluations of brainstem and spinal tissues, we will use the microinjection of selective neurotoxins and chemogenetic DREADDs to study the function of brainstem pain regulatory centers after TBI. In the final aim we use two models of polytrauma combining TBI with soft tissue incision and, separately, tibial fracture. We hypothesize that clinically available modulators of noradrenergic and serotonergic signaling will reduce nociceptive sensitization, enhance descending pain modulation and reduce the interaction of peripheral trauma and TBI on neuroinflammation and the expression of several pain-related spinal genes. By reducing chronic pain-related changes we further hypothesize that functional measures, anxiety and cognitive changes will all be less affected after the injuries. At the time of completion of the project we expect to understand better how TBI, peripheral injury and the combination of injuries cause chronic pain. In the process of this evaluation we will delineate the roles of dysfunction in specific brainstem pain modulating centers. We anticipate being in position to plan translational human studies using some of the same agents and approaches employed preclinically.